Abstract The long term goal of this research proposal is to develop a vaccine for respiratory syncytial virus (RSV), human parainfluenza virus type 1 (hPIV-1) and human parainfluenza virus type 3 (hPIV-3), the leading causes of hospitalizations for viral respiratory tract diseases in infants and young children. Sendai virus is a mouse respiratory pathogen that merits consideration as a candidate for an hPIV-1 vaccine because it is closely related to hPIV-1 in sequence, structure and antigenicity. To expand the immunization potential of Sendai virus to RSV and hPIV-3, two recombinant Sendai viruses were produced, one encompassing the RSV F passenger gene, and the second encompassing the HN gene of hPIV-3. Intranasal vaccination with these Sendai viruses together protects cotton rats against hPIV-1, hPIV-3 and RSV challenge. This preclinical data combined with our previous demonstration that intranasal administration of live, unmodified Sendai virus is safe in adults and preliminarily in young children makes a compelling case for evaluation of recombinant Sendai virus vaccine. Testing will begin with a phase I trial in adults and toddlers who are seropositive for hPIV-1, and ultimately advance to hPIV-1 seronegative infants, the target population of the vaccine. The proposed phase I clinical trial of the recombinant Sendai virus vaccine will build upon our experience with our published phase I trial of unmodified Sendai virus vaccine in adults and our currently accruing phase I pediatric trial of the same vaccine. The investigative team is comprised of senior clinical and basic science investigators with highly relevant experience for the present proposal. The Translational Trials Unit at St. Jude Children's Research Hospital is ideally suited to conduct the proposed trial. This planning grant proposal will yield a carefully designed phase I clinical trial and U01 grant application to evaluate a highly promising recombinant Sendai virus vaccine for three important pediatric viral respiratory pathogens.